Combination Therapies to Defeat Melanoma Resistance

击败黑色素瘤耐药性的联合疗法

• 批准号: 10261395
• 负责人: ANTONI RIBAS
• 金额: $ 260.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10261395
• 关键词: Address; Antigen Presentation Pathway; BRAF gene; Back; Bioinformatics; Biological Models; Biology; Caspase; Cell Death; Clinic; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Communities; Databases; Development; Exclusion; Experimental Models; Genomics; Goals; Immune; Immune Targeting; Immunotherapy; Institute of Medicine (U.S.); Interferon Type II; Iron; Knowledge; Lead; Letters; MAP Kinase Gene; MEKs; Malignant Neoplasms; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Organ; PD-1 blockade; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Program Research Project Grants; Published Comment; Research; Research Project Grants; Resistance; Sampling; Signal Transduction; Site; System; T-Lymphocyte; Testing; Therapeutic; Tissue Model; addiction; anti-PD-1; anti-PD1 therapy; base; clinical translation; combinatorial; cytokine; design; epigenomics; immune checkpoint blockade; improved; in vivo; inhibitor/antagonist; innovation; melanoma; mouse model; mutant; new combination therapies; next generation; novel; novel therapeutics; patient derived xenograft model; pre-clinical; prevent; programs; research clinical testing; resistance mechanism; response; statistics; targeted treatment

OVERALL ABSTRACT This is the A1 re-submission of a new Program Project Grant (PPG) focused on studying how advanced melanoma resists targeted therapies and immunotherapies, either upfront or after a period of response, and this information is aimed at defining the vulnerabilities that provide new therapeutic opportunities. Project 1 (Roger Lo) focuses on the study of resistance of NRASMUT melanomas to targeted therapies and immunotherapies. Studies will focus on discovering and co-targeting genomic, epigenomic and/or signaling alterations causative of MEK inhibitor (MEKi) resistance; exploiting MEKi-addiction of MEKi-resistant clones; and identifying immune targets to augment MEKi efficacy and suppress MEKi resistance in vivo in NRASMUT melanomas. Project 2 (Thomas Graeber) focuses on studying molecular mechanisms and targeting of the ferroptosis sensitivity of dedifferentiated melanomas in preclinical models. In addition, this project will also define and target master regulatory programs underlying melanoma dedifferentiation. Project 3 (Antoni Ribas) focuses on studying primary and acquired resistance to PD-1 blockade immunotherapy, especially defining mutations in the interferon gamma and antigen presentation pathways, as well as reversing T cell exclusion from cancers. The understanding of these resistance mechanisms will rationalize combinatorial therapies to be tested in preclinical mouse models. The three projects are supported by three cores, the Administrative and Statistics Core (Antoni Ribas), the Biospecimen Core (Begonya Comin-Anduix) and the Patient-Derived Xenograft (PDX)/Syngeneic Mouse Core (Gatien Moriceau). The proposed research addresses scientific problems that require integrated and collaborative teamwork. In Project 1, the study of MAPK inhibitor addiction, resulting in sensitivity to drugs that induce parthanatos (a caspase-independent mode of cell death), can be applied to the melanoma dedifferentiation states studied in Project 2 and will synergize with immunotherapies studied in Project 3. Similarly, in Project 2, the dedifferentiated melanoma phenotype, which is a resistance mechanism to MAPK inhibitors and also induced by T cell-released cytokines, leads to sensitivity to ferroptosis- (an iron-dependent form of nonapoptotic cell death) inducing agents. This resistance mechanism will be explored in NRAS mutant melanoma in Project 1 and across melanoma with resistance to anti-PD1 in Project 3. Reciprocally, Project 3 will seek to integrate the new concepts and models from Projects 1 and 2, given the likely immune effects of inducing these new forms of cell death. This collaborative research will require sharing the patient-derived tissues, model systems, and therapeutic regiments acquired and developed in each Project, facilitated by Cores B and C, and statistical design and support from Core A. 1

总体摘要 这是A1重新提交的新计划项目补助金(PPG)，重点是研究如何高级 黑色素瘤抵抗靶向治疗和免疫治疗，无论是在前期还是在一段时间的反应之后，以及 这些信息旨在确定提供新的治疗机会的脆弱性。项目1 (Roger Lo)专注于NRASMUT黑色素瘤对靶向治疗的耐药性研究 免疫疗法。研究将集中于发现和共同靶向基因组、表观基因组和/或信号转导 引起MEK抑制剂(Meki)抗性的变化；利用Meki成瘾的Meki抗性克隆； 在NRASMUT体内寻找增强Meki疗效和抑制Meki耐药性的免疫靶点 黑色素瘤。项目2(Thomas Graeber)专注于研究分子机制和靶向 临床前模型中去分化黑色素瘤的铁性下垂敏感性。此外，该项目还将 定义和定位黑色素瘤去分化的主要调控程序。项目3(安东尼·里巴斯) 重点研究PD-1阻断免疫疗法的原发和获得性耐药性，特别是 干扰素-γ和抗原提呈途径的突变以及逆转T细胞排斥 来自癌症的。对这些耐药机制的理解将使联合治疗合理化 在临床前小鼠模型中进行了测试。这三个项目得到三个核心的支持，即行政和 统计核心(Antoni Ribas)、生物谱核心(Begonya Comin-Anduix)和患者派生的 异种移植(PDX)/同基因小鼠核心(Gatien Moriceau)。 这项拟议的研究解决了需要整合和协作的团队合作的科学问题。在……里面 项目1，MAPK抑制剂成瘾研究，导致对诱发甲状旁腺激素的药物的敏感性(a Caspase非依赖的细胞死亡模式)，可以应用于在 项目2，并将与项目3中研究的免疫疗法协同作用。同样，在项目2中， 去分化黑色素瘤表型，这是MAPK抑制剂的耐药机制，也是诱导 通过T细胞释放的细胞因子，导致对铁下垂(一种铁依赖的非凋亡细胞形式)的敏感性 致死)诱导剂。在项目1中，将在NRAS突变黑色素瘤中探索这种耐药机制 以及在项目3中对抗PD1产生耐药性的黑色素瘤。反过来，项目3将寻求整合 项目1和2中的新概念和模型，考虑到诱导这些新的 细胞死亡的形式。这种协作研究将需要共享患者来源的组织、模型系统、 在每个项目中获得和开发的治疗方案，由核心B和C协助，以及 统计设计和核心A的支持。 1